Skip to main content

Advertisement

SpringerLink
Log in

Expert Discussion of the Role of Rate Constant Versus Clearance Approaches to Define Drug Pharmacokinetics: Theoretical and Clinical Considerations

  • Tutorial
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

This article provides a dialogue covering an ongoing controversy on the use of clearance versus rate constant approaches for model parameterization when assessing pharmacokinetic (PK) data. It reflects the differences in opinions that can exist among PK experts. Importantly, this discussion extends beyond theoretical arguments to demonstrate how these different approaches impact the analysis and interpretation of data acquired in clinical situations. By not shying away from such dialogues, this article showcases how dissimilarity in well-grounded perspectives can influence how one applies PK and mathematical principles.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Rowland M, Benet LZ, Graham GG. Clearance concepts in pharmacokinetics. J Pharmacokinet Biopharm. 1973;1(2):123–36.

    Article  CAS  Google Scholar 

  2. Mehvar R. Teachers topics. The relationship among pharmacokinetic parameters: effects of altered kinetics on the drug plasma concentration–time profiles. Am J Pharm Educ. 2004;68(2):article 36.

    Google Scholar 

  3. Mehvar R. Interdependency of pharmacokinetic parameters: a chicken-and-egg problem? Not! J Pharm Pharm Sci. 2006;9(1):113–8.

    CAS  PubMed  Google Scholar 

  4. PharmPK Discussion – Clearance vs rate constant (2001). https://www.pharmpk.com/PK01/PK2001055.html. Last visited June 1, 2019.

  5. PharmPK Discussion – Clearance and elimination (2006a). https://www.pharmpk.com/PK06/PK2006120.html. Last visited June 1, 2019.

  6. PharmPK Discussion – What is Clearance? (2006b). https://www.pharmpk.com/PK06/PK2006599.html. Last visited June 1, 2019.

  7. PharmPK Discussion – A question of clearance (2009). https://www.pharmpk.com/PK09/PK2009003.html. Last visited June 1, 2019.

  8. PharmPK Discussion – A question of clearance (2010a). https://www.pharmpk.com/PK10/PK2010002.html. Last visited June 1, 2019.

  9. PharmPK Discussion – Volume of Distribution and Clearance (2010b). https://www.pharmpk.com/PK10/PK2010316.html. Last visited June 1, 2019.

  10. Jelliffe R. Challenges in individualizing drug dosage for intensive care unit patients: is augmented renal clearance what we really want to know? Some suggested management approaches and clinical software tools. Clin Pharmacokinet. 2016;55:897–905. https://doi.org/10.1007/s40262-016-0369-4.

    Article  CAS  PubMed  Google Scholar 

  11. Proost JH. Comment on: “challenges in individualizing drug dosage for intensive care unit patients: is augmented renal clearance what we really want to know? Some suggested management approaches and clinical software tools”. Clin Pharmacokinet. 2017;56:311–2. https://doi.org/10.1007/s40262-016-0480-6.

    Article  PubMed  Google Scholar 

  12. Jelliffe R and Bayard D. New perspectives in clinical pharmacokinetics-1: the importance of updating the teaching in pharmacokinetics that both clearance and elimination rate constant approaches are mathematically proven equally valid. AAPS J. 2018; 20(2). DOI: https://doi.org/10.1208/s12248-018-0185-x.

  13. Goodwin G, Payne R. Dynamic system identification: experiment design and data analysis. New York: Academic Press; 1977. p. 50. (Theorem 3.4.1)

    Google Scholar 

  14. Jelliffe R, Neely M, editors: “Individualized drug therapy for patients—basic foundations, relevant software, and clinical applications”. Imprint: Academic Press. Release Date: November 15, 2016. Print Book ISBN: 9780128033487.

  15. Jelliffe R, Bayard D, Milman M, Van Guilder M, Schumitzky A. Achieving target goals most precisely using nonparametric compartmental models and “multiple model” design of dosage regimens. Therap Drug Monit. 2000;22:346–53.

    Article  CAS  Google Scholar 

  16. Bayard D, Jelliffe R. A Bayesian approach to tracking patients having changing pharmacokinetic parameters. J Pharmacokinet Pharmacodyn. 2004;31:75–107.

    Article  Google Scholar 

  17. Bellman R. Adaptive control processes - a guided tour. Princeton University Press, Princeton, New Jersey; 1961. pp. 255. https://doi.org/10.1002/nav.3800080314.

  18. Neely M, van Guilder M, Yamada W, Schumitzky A, Jelliffe R. Accurate detection of outliers and subpopulations with Pmetrics, a nonparametric and parametric pharmacometric modeling and simulation package for R. Therap Drug Monit. 2012;34:467–76.

    Article  Google Scholar 

  19. Udy A, Putta M, Shanmugathasana S, Roberts J, Lipman J. Augmented renal clearance in the intensive care unit: an illustrative case series. Int J Antimicrob Agents. 2010;35:606–8.

    Article  CAS  Google Scholar 

  20. Mahmoud SH, Shen C. Augmented renal clearance in critical illness: an important consideration in drug dosing. Pharmaceutics. 2017;9(3):36. https://doi.org/10.3390/pharmaceutics9030036.

    Article  CAS  PubMed Central  Google Scholar 

  21. Haug III MT, Slugg PH. Antibiotic pharmacokinetics. In: Sivak E., Higgins, T., Seiver, A., eds. The High Risk Patient: Management of the Critically Ill. Baltimore: Williams & Wilkin, 1995, pp 1338-64. ISBN 0-683-07785-6

  22. Jelliffe RW, Milman M, Schumitzky A, Bayard D, Van Guilder M. A two-compartment population pharmacokinetic-pharmacodynamic model of digoxin in adults, with implications for dosage. Ther Drug Monit. 2014;36:387–93. https://doi.org/10.1097/FTD.0000000000000023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jelliffe R. The role of digitalis pharmacokinetics in converting atrial fibrillation and flutter to regular sinus rhythm. Clin Pharmacokinet. 2014;53:397–407. https://doi.org/10.1007/s40262-014-0141-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bellman R, Astrom XXX. On structural Identifiability. Math Biosci. 1970;7:329–39.

    Article  Google Scholar 

  25. Reuning R, Sams R, Notari. Role of pharmacokinetics in drug dosage adjustment. 1. Pharmacologic effect kinetics and apparent volume of distribution of digoxin. J Clin Pharmacol. 1973;13:127–41.

    CAS  Google Scholar 

  26. Jelliffe R. Estimation of creatinine clearance in patients with unstable renal function, without a urine specimen. Am J Nephrol. 2002;22:320–4.

    Article  Google Scholar 

  27. Bustad A, Terziivanov D, Leary R, Port R, Schumitzky A, Jelliffe R. Parametric and nonparametric population methods: their comparative performance in analysing a clinical data set and two Monte Carlo simulation studies. Clin Pharmacokinet. 2006;45:365–83.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Office of New Animal Drug Evaluation, HFV-100, Center for Veterinary Medicine, Rockville, Maryland, 20855, USA

    Marilyn N. Martinez

  2. Laboratory of Applied Pharmacokinetics and Bioinformatics, Keck School of Medicine, Children’s Hospital of Los Angeles, University of Southern California, Los Angeles, California, USA

    Roger W. Jelliffe

  3. Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen Antonius Deusinglaan, 19713 AV, Groningen, The Netherlands

    Johannes H. Proost

Authors
  1. Marilyn N. Martinez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roger W. Jelliffe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Johannes H. Proost
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marilyn N. Martinez.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This communication reflects the opinion of the author and does not reflect views or policy of the FDA.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martinez, M.N., Jelliffe, R.W. & Proost, J.H. Expert Discussion of the Role of Rate Constant Versus Clearance Approaches to Define Drug Pharmacokinetics: Theoretical and Clinical Considerations. AAPS J 22, 25 (2020). https://doi.org/10.1208/s12248-019-0407-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12248-019-0407-x

Keywords

Search

Navigation